BIG Scientists are Finalists for Breakthrough of the Year

Neuroscientists found to their surprise that the lymphatic system–the network of vessels that helps clear waste in the body and circulate key immune cells–exists in the brain. The discovery (which some researchers argue is a rediscovery) should stimulate a closer look at links between the immune system and the brain.

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A major discovery about the human brain made at the University of Virginia School of Medicine has been named a finalist for Breakthrough of the Year by Science, one of the world’s most prestigious scientific journals. The award aims to recognize the “most momentous scientific discovery, development or trend of 2015.”

UVA’s shocking discovery of a direct connection between the brain and the immune system — a connection long thought not to exist — is one of 10 finalists selected by the publication’s writers and editors. The journal will announce the winner Dec. 17. In the meantime, readers can see the list of finalists and vote for their pick for the People’s Choice award by visiting

But hurry — voting closes Sunday.

About UVA’s Discovery

UVA researchers Jonathan Kipnis, PhD, and Antoine Louveau, PhD, overturned decades of textbook teaching when they discovered previously unknown vessels connecting the brain directly to the lymphatic system. The finding redrew the map of the human lymphatic system and struck down long-held beliefs about how the immune system functions in the brain. The discovery could have profound implications for a huge array of neurological diseases, from multiple sclerosis to Alzheimer’s disease.

 Kipnis is a professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia. Louveau is research scientist who joined Kipnis’ lab as a postdoctoral fellow.

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In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist.

That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis.


“Instead of asking, ‘How do we study the immune response of the brain?,’ ‘Why do multiple sclerosis patients have the immune attacks?,’ now we can approach this mechanistically – because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels,” said Jonathan Kipnis, a professor in U.Va.’s Department of Neuroscience and director of U.Va.’s Center for Brain Immunology and Glia. “It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can’t be studied. But now we can ask mechanistic questions.”

He added, “We believe that for every neurological disease that has an immune component to it, these vessels may play a major role. [It’s] hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component.”

Kevin Lee, who chairs the Department of Neuroscience, described his reaction to the discovery by Kipnis’ lab: “The first time these guys showed me the basic result, I just said one sentence: ‘They’ll have to change the textbooks.’ There has never been a lymphatic system for the central nervous system, and it was very clear from that first singular observation – and they’ve done many studies since then to bolster the finding – that it will fundamentally change the way people look at the central nervous system’s relationship with the immune system.”

Even Kipnis was skeptical initially. “I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped,” he said. “I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not.”

The discovery was made possible by the work of Antoine Louveau, a postdoctoral fellow in Kipnis’ lab. The vessels were detected after Louveau developed a method to mount a mouse’s meninges – the membranes covering the brain – on a single slide so that they could be examined as a whole. “It was fairly easy, actually,” he said. “There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn’t have worked.”

After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed.

The soft-spoken Louveau recalled the moment: “I called Jony [Kipnis] to the microscope and I said, ‘I think we have something.’”

As to how the brain’s lymphatic vessels managed to escape notice all this time, Kipnis described them as “very well hidden” and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. “It’s so close to the blood vessel, you just miss it,” he said. “If you don’t know what you’re after, you just miss it.

“Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris,” Kipnis noted. Harris is an assistant professor of neuroscience and a member of the Center for Brain Immunology and Glia. Kipnis also saluted the “phenomenal” surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.

The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it.

For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore.

And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.

The findings have been published online by the prestigious journal Nature and will appear in a forthcoming print edition. The article’s authors are Louveau, Smirnov, Timothy J. Keyes, Jacob D. Eccles, Sherin J. Rouhani, J. David Peske, Noel C. Derecki, David Castle, James W. Mandell, Lee, Harris and Kipnis.

The study was funded by National Institutes of Health grants R01AG034113 and R01NS061973. Louveau was a fellow of Fondation pour la Recherche Medicale.

BIG Identifies Major Genetic Causes of Schizophrenia

Researchers at the School of Medicine will seek to identify the genetic causes of schizophrenia as part of a major project funded by the National Institute of Mental Health to better understand how genetic variation in brain cells affects human health and disease.

B.I.G. Researcher Mike McConnell, PhD, of UVA’s Department of Biochemistry and Molecular Genetics, will use a cutting-edge technique known as single-cell genome sequencing to examine brain samples both from people who had schizophrenia and a control group of people who did not. The technique allows scientists to examine the genetic makeup of a single cell, a vital tool in the wake of the discovery by McConnell and his collaborators that the neurons in the brain are unexpectedly varied in their genetic makeup.

That variety of genomes within the brain – or “mosaicism,” as it’s called – could hold the secret to schizophrenia, and may explain why researchers have found it so difficult to determine the genes responsible. “Right now, the genetic origins of schizophrenia are incredibly elusive,” McConnell said. “By looking at the brain and by understanding the genetic causes, we would hope to make better drugs or have better insights into therapeutic regimens to help these patients.”

McConnell will conduct single-cell sequencing with his former colleague Fred H. Gage, PhD, of the Salk Institute. This work will be performed on selected cases from the world’s leading schizophrenia brain bank, the Lieber Institute for Brain Development at Johns Hopkins University. Human genome experts at the University of Michigan, meanwhile, will examine the genomes of pools of cells using what is known as bulk sequencing.

Each technique has its advantages, McConnell explained: “With bulk sequencing, you get better resolution of any event that’s happening, but the events needs to be common. You can’t pick up rare events. You can pick up smaller changes, but the change needs to be shared among many cells,” he said. “Whereas in single cells, we don’t have quite the resolution, but we can pick up things that are one-off events, and rare and different. Since we don’t know which of those two differences it will be, we’re doing both.”

“The idea is basically to look at well-paired samples of controls and schizophrenics and look at differences in the mosaic,” McConnell said. “Those differences could be gross differences … the type of thing we’ll pick up with bulk sequencing, or they could be differences that can only be detected through single-cell sequencing.”

The research is being funded by the National Institutes of Health’s National Institute of Mental Health with a five-year grant that could top $11.5 million.

The participating researchers are setting up a major data sharing initiative to make their findings quickly available to other researchers and the public, in line with the NIMH’s desire to make cutting-edge research accessible as soon as possible.